Microvascular oxidative stress in the triad of cardiovascular, metabolic and renal disease
Using a translational approach (in vitro and in vivo microperfusion systems, genetically modified mice, and clinical trials) our projects aim to further characterize mechanisms for reactive oxygen species and nitric oxide formation, interaction and influence on renal, cardiovascular and metabolic functions in health and disease.
Cardiovascular disease and diabetes are increasing health problems worldwide, resulting in an enormous economic burden to society. To better understand, prevent and cure these lifestyle diseases it is necessary to research the underlying mechanisms that allow the diseases to arise.
The kidneys set the long-term level of blood pressure by regulating peripheral vascular resistance and body fluid volume. It is suggested that impaired renal function importantly contributes to the development of hypertension, which is a main risk factor for morbidity and mortality complications from cardiovascular diseases and type 2 diabetes.
Moreover, renal dysfunction is commonly described as a complication of metabolic syndrome, but new knowledge shows that renal disease actually may antecede the syndrome. Approximately 25 per cent of the worlds adult population has the metabolic syndrome (cluster of obesity, dyslipidemia, hyperglycemia, and hypertension). These individuals are at a higher risk of developing cardiovascular disease and type 2 diabetes.
Renal oxidative stress and nitric oxide in cardiovascular disease and diabetes
Emerging evidence suggests that renal oxidative stress and nitric oxide deficiency is associated with cardiovascular disease and diabetic complications. Currently the mechanisms are not clear, but imbalance between reactive oxygen species and nitric oxide (in favour of the former) may impair renal autoregulatory function, and thus impact on renal blood flow and glomerular filtration.
Research in our laboratory
Using a translational approach (in vitro and in vivo microperfusion systems, genetically modified mice, and clinical trials) our projects aim to further characterize mechanisms for reactive oxygen species and nitric oxide formation, interaction and influence on renal, cardiovascular and metabolic functions in health and disease. It is hypothesized that oxidative stress and nitric oxide deficiency are linked to renal dysfunction and metabolic syndrome, and increase the risk for cardiovascular disease and type 2 diabetes. In the kidney, increased reactive oxygen species and/or decreased nitric oxide production may increase preglomerular resistance and promote fluid retention, and thus contribute to disease.
Renal oxidative stress may impair autoregulation and consequently cause hypertension. Such processes may be counteracted by stimulation of NO or inhibition of ROS production. Conditions with high salt-intake, elevated angiotensin II (Ang II) levels, or increased adenosine A-{1} receptor signaling may stimulate ROS production, and consequently impair renal, cardiovascular and metabolic regulation.
Group members
Mattias Carlström – Research group leader, Assistant Professor
Isabel Cordero – Postdoc
Josiane de Campos Cruz – Postdoc
Huirong Han – Postdoc
Rafael Krmar – Associated
Luciano Leite Paulo – Associated, PhD Student
Maria Peleli – Associated, PhD
Erik Persson – Professor emeritus
Gensheng Zhang – Visiting Researcher
Zhengbing Zhuge – PhD Student
Group members outside KI:
Ammar Farman Al-Mashhadi – PhD, Dept of Medical Cell Biology, Uppsala
Andrei L. Kleschyov – Visiting Researcher
Ting Yang – Associated MD, PhD
Projects
Project 1: Role of NADPH oxidase and superoxide dismutase (SOD) in renal, cardiovascular and metabolic regulation
NADPH oxidases are the primary source of superoxide (O2-) production, whereas SOD-isoforms play an important role in eliminating O2-. NOX2 is the major NADPH oxidase isoform in the macula densa cells of the kidney, and we have shown that NOX2-deficient mice display attenuated renal afferent arteriolar and blood pressure responses to Ang II infusion.
Moreover, we have described a link between SOD1-deficiency and salt-sensitive hypertension, impaired kidney function and cardio-renal injuries. This project aims at further characterizing the role and mechanisms of how different NADPH oxidases and SOD isoforms regulate renal, cardiovascular and metabolic functions in health and disease. Our findings indicate an important role of NADPH and SOD systems in regulating renal microcirculation and hence blood pressure. It is suggested that strategies targeting signaling of specific NADPH oxidases or SOD isoforms may restore the balance between reactive oxygen species and nitric oxide, and thus become valuable therapeutics.
Project 2: Role of adenosine A1 and A2 receptors in renal, cardiovascular and metabolic regulation
Adenosine is an important modulator of many physiological processes, including renal, cardiac and metabolic functions. There are four known adenosine receptors (A1, A2A, A2B, A3), which have all been demonstrated in the kidney. In renal afferent arterioles, activation of A1 receptors mediates vasoconstriction whereas A2 receptors mediate vasodilatation.
It has been shown that TGF is mediated via activation of adenosine A1 receptors. Earlier studies have suggested a link between A1 receptor expression/activity and oxidative stress, which may enhance TGF and preglomerular reactivity and thus increase blood pressure. In recent studies, we showed that stimulation of A2 receptors in the juxtaglomerular apparatus blunts TGF, by a mechanism that involves stimulation of eNOS-derived nitric oxide. This project aims at further characterizing the role and mechanisms for how different adenosine receptors regulate renal, cardiovascular and metabolic functions in health and disease. It is suggested that treatment strategies that inhibit A1 receptors, or stimulate A2 receptors, improve the outcome of renal and cardiovascular disease by modulating the formation or interaction between reactive oxygen species and nitric oxide in the kidney.
Project 3: Role of nitrate-nitrite-NO pathway in renal, cardiovascular and metabolic regulation
The inorganic anions nitrate and nitrite have long been considered as inert oxidative end products of endogenous nitric oxide (NO) metabolism. However, research conducted during the last years reveals they can undergo bioconversion to form NO by NOS-independent mechanisms. In collaboration with Professors Lundberg and Weitzberg at the Department of Physiology and Pharmacology, Karolinska Institutet, we showed that nitrate supplementation, in a dose that resembles the nitrate content of the DASH-trial diet, reduced blood pressure in healthy volunteers and in rats to a similar degree as observed in intervention-trials with fruit and vegetables. Moreover, dietary nitrate supplementation had therapeutic effects in an established model of renal and cardiovascular disease and reversed features of metabolic syndrome in aged eNOS-deficient mice.
At present, the target organ for nitrate-nitrite-NO conversion is not known. However, our findings indicate that stimulation of a nitrate-nitrite-NO pathway may influence kidney function. This project aims at further characterizing underlying mechanisms for the therapeutic effects associated with nitrate and nitrite supplementation. It is suggested that nitrate and nitrite may modulate reactive oxygen species and nitric oxide balance in the kidney, and hence prevent or halt progression of renal and cardiovascular disease, as well as type 2 diabetes.
Significance
Further mechanistic studies are necessary for developing cost-efficient principles to prevent or treat cardiovascular disease and type 2 diabetes. These projects have a translational design, ranging from in vitro microperfusion experiments to intervention studies in humans, and aims at further characterizing the role and mechanisms for reactive oxygen species and nitric oxide signaling in health and disease.
Our strongest belief is that findings will advance our knowledge in a rapidly developing field. Results with nitrate and nitrite supplementation are promising and we believe that strategies decreasing reactive oxygen species or increase nitric oxide production may have implications for novel nutrition based preventive and cost-efficient therapeutic strategies in cardiovascular disease and type 2 diabetes.
Collaborations
International collaborators of interest
- Dr Christopher Wilcox, William Welch & Anton Wellstein (Georgetown University, Washington DC): Oxidative stress, renal hypertension and diabetes & Clinical trial in US
- Dr Enyin Lai (Zhejiang University, China): Renal microvasculature & Clinical trials in China
- Dr Ruisheng Liu (University of Mississippi Medical Center, Jackson, MS): Macula densa signal
- Dr. Andreas Patzak & Mauricio Sendeski (Charité University, Berlin): Renal microvasculature
- Dr Tom Teerlink & Peter G. Scheffer (VU University Medical Centre, Amsterdam): Oxidative stress
- Dr Boye Jensen & Ole Skøtt (University of Southern Denmark, Odense): Renin-Angiotensin analysis
- Dr Maristela L. Onozato (Massachusetts General Hospital, Boston, USA): Renal morphology
- Dr Kenneth A. Jacobson (National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, USA): Novel and highly adenosine receptor analogues
National collaborators of interest
- Dr Rafael Krmar, Jakob Stenman, Thomas Gustfsson, Peter Bárány, Annika Wernersson (Karolinska University Hospital): Ongoing Clinical trial
- Dr Tryggve Nevéus, Peter Flacker, Arne Stenberg (Akademiska Hospital): Ongoing Clinical trial
- Dr Jon Lundberg & Eddie Weitzberg (Karolinska Institutet): Nitrate-nitrite-NO pathway
- Dr Robert Harris (Karolinska Institutet): Diabetes and inflammation (flow cytometry analysis)
- Dr Agneta Richter Dahlfors (Karolinska Institutet): Bacteria in renal inflammatory responses
- Dr Leif Jansson (Uppsala University): Islet function in diabetes & clinical trial
- Dr Erik Persson (Uppsala University): Renal function in hypertension
- Dr Bertil Fredholm (Karolinska Institutet): Adenosine receptors
- Dr Erik Larsson (Uppsala University): Evaluation of histology, morphology & immunohistochemistry
Collaboration with the Community
World Action on Salt and Health (WASH): As a member of this organization we aim to achieve a reduction in dietary salt intake around the world from the current intake of 10-15g/day to the World Health Organization (WHO) target of 5g/day. This fall in salt intake and the resulting fall in blood pressure would lead to major reductions in both incidents of, and deaths from Cardiovascular Disease (CVD) i.e. stroke, heart failure and heart attacks, with a major reduction in the disability that results from CVD. We have discussions with the food industry and government and also try to reach out to the households. This spring WASH Sweden organized a joint meeting together with Livsmedelsverket in Uppsala.
National Kidney Foundation (NKF): As a member of this organization we aim to enhance the lives of everyone with, at risk of or affected by kidney disease. NKF, a major voluntary non-profit health organization, is dedicated to preventing kidney and urinary tract diseases, improving the health and well-being of individuals and families affected by kidney disease and increasing the availability of all organs for transplantation. NKF has been providing help and hope to kidney patients and their families since 1950. Today, with local offices across the country, NKF is meeting the growing public health challenge of chronic kidney disease with a range of vital programs and services for the public, patients and healthcare professionals.
Financial support
- The Swedish Heart-Lung Foundation
- The Swedish Research Council (VR)
- Jeanssons Foundation
- The Lars Hierta Memorial Foundation
- Swedish Society for Medical Research
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10 most important original publications
Abrogation of adenosine A1 receptor signalling improves metabolic regulation in mice by modulating oxidative stress and inflammatory responses.
Yang T, Gao X, Sandberg M, Zollbrecht C, Zhang XM, Hezel M, et al
Diabetologia 2015 Jul;58(7):1610-20
Inorganic nitrite attenuates NADPH oxidase-derived superoxide generation in activated macrophages via a nitric oxide-dependent mechanism.
Yang T, Peleli M, Zollbrecht C, Giulietti A, Terrando N, Lundberg JO, et al
Free Radic. Biol. Med. 2015 Jun;83():159-66
NADPH oxidase in the renal microvasculature is a primary target for blood pressure-lowering effects by inorganic nitrate and nitrite.
Gao X, Yang T, Liu M, Peleli M, Zollbrecht C, Weitzberg E, et al
Hypertension 2015 Jan;65(1):161-70
Cross-talk Between Nitrate-Nitrite-NO and NO Synthase Pathways in Control of Vascular NO Homeostasis.
Carlström M, Liu M, Yang T, Zollbrecht C, Huang L, Peleli M, et al
Antioxid. Redox Signal. 2015 Aug;23(4):295-306
Adenosine A2A receptor activation attenuates tubuloglomerular feedback responses by stimulation of endothelial nitric oxide synthase.
Carlström M, Wilcox CS, Welch WJ
Am. J. Physiol. Renal Physiol. 2011 Feb;300(2):F457-64
Dietary nitrate attenuates oxidative stress, prevents cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension.
Carlström M, Persson AE, Larsson E, Hezel M, Scheffer PG, Teerlink T, et al
Cardiovasc. Res. 2011 Feb;89(3):574-85
Superoxide dismutase 1 limits renal microvascular remodeling and attenuates arteriole and blood pressure responses to angiotensin II via modulation of nitric oxide bioavailability.
Carlström M, Lai EY, Ma Z, Steege A, Patzak A, Eriksson UJ, et al
Hypertension 2010 Nov;56(5):907-13
Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice.
Carlström M, Larsen FJ, Nyström T, Hezel M, Borniquel S, Weitzberg E, et al
Proc. Natl. Acad. Sci. U.S.A. 2010 Oct;107(41):17716-20
Nitric oxide deficiency and increased adenosine response of afferent arterioles in hydronephrotic mice with hypertension.
Carlström M, Lai EY, Steege A, Sendeski M, Ma Z, Zabihi S, et al
Hypertension 2008 May;51(5):1386-92
Uninephrectomy in young age or chronic salt loading causes salt-sensitive hypertension in adult rats.
Carlström M, Sällström J, Skøtt O, Larsson E, Persson AE
Hypertension 2007 Jun;49(6):1342-50
Other selected publications
Renal Autoregulation in Health and Disease.
Carlstrom M, Wilcox CS, Arendshorst WJ.
Physiol Rev 95:405-511; 2015.
Roles of dietary inorganic nitrate in cardiovascular health and disease.
Lundberg JO, Carlstrom M, Larsen FJ, Weitzberg E.
Cardiovasc Res 89:525-532; 2011.
Important role of NAD(P)H oxidase 2 in the regulation of the tubuloglomerular feedback.
Carlstrom M, Persson AE.
Hypertension 53:456-457; 2009.
Cover images
Renal Autoregulation in Health and Disease.
Carlstrom M, Wilcox CS, Arendshorst WJ.
Physiol Rev 95:405-511; 2015.
Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice.
Carlstrom M, Larsen FJ, Nystrom T, Hezel M, Borniquel S, Weitzberg E, Lundberg JO.
Proc Natl Acad Sci U S A 107:17716-17720; 2010.
Recent contributions to scientific meetings
Adenosine A3 Receptors Regulate Oxidative Stress and Inflammatory Responses in a Model of Hypertension and Renal Disease.
Yang T, Hezel M, Peleli M, Zhang X, Terrando N, Fredholm B, Carlström M.
Am. Heart Association, HBPR2014, P086, 2014
Renal Denervation Attenuates Salt-Sensitive Hypertension and Oxidative Stress in Rats with Unilateral Hydronephrosis.
Peleli M, Al-Mashadi A, Yang T, Carlstrom M.
Am. Heart Association, HBPR2014, P077, 2014
Role of gut microbiota in modulating the anti-inflammatory and antioxidative effects of dietary nitrate.
Yang T, Huang L, Gao X, Lundberg J, Weitzberg E, Persson AEG, Carlström M.
Nitric Oxide, 31:S16, 2013
Open positions
Applications for doctoral programme and postdoctoral fellow training are welcome, for the study of nitric oxide and free radical signaling in cardiovascular, renal and metabolic disorders. Background/experience in physiology and pharmacology and/or molecular biology is favourable, but not necessary for applying. Please send a letter of interest and CV to Mattias Carlström, group leader. We may assist with applications for external support in form of postdoctoral or doctoral student fellowships.